The GABA modulating and GABA‐mimetic actions of the general anaesthetic etomidate were examined in voltage‐clamp recordings performed on Xenopus laevis oocytes induced, by cRNA injection, to express human recombinant γ‐aminobutyric acid_A (GABA_A) receptor subunits. Currents mediated by recombinant receptors with the ternary subunit composition α_xβ_yγ_2L (where x=1,2,3 or 6 and y=1 or 2), in response to GABA applied at the appropriate EC₁₀, were enhanced by etomidate in a manner that was dependent upon the identity of both the α and β subunit isoforms. For the β₂‐subunit containing receptors tested, the EC₅₀ for the potentiation of GABA‐evoked currents by etomidate (range 0.6 to 1.2 μm) was little affected by the nature of the α subunit present within the hetero‐oligomeric complex. However, replacement of the β₂ by the β₁ subunit produced a 9–12 fold increase in the etomidate EC₅₀ (6 to 11 μm) for all α‐isoforms tested. For α₁, α₂ and α₆, but not α₃‐subunit containing receptors, the maximal potentiation of GABA‐evoked currents by etomidate was greater for β₂‐ than for β₁‐subunit containing receptors. This was most clearly exemplified by receptors composed of α₆β₁γ_2L compared to α₆β₂γ_2L subunits, where a maximally effective concentration of etomidate potentiated currents evoked by GABA at EC₁₀ to 28±2% and 169±4% of the maximal GABA response, respectively. For α₁ subunit‐containing receptors, the potency and maximal potentiating effect of either pentobarbitone or propofol was essentially unaffected by the β subunit isoform contained within the receptor complex. The potency of the anaesthetic neurosteroid 5α‐pregnan‐3α‐ol‐20‐one was marginally higher for β₁ rather than the β₂ subunit‐containing receptor, although its maximal effect was similar at the two receptor isoforms. The GABA‐mimetic action of etomidate was supported by β₂‐ but not β₁‐subunit containing receptors, whereas that of pentobarbitone or propofol was evident with either β isoform. For β₂‐subunit containing receptors, both the agonist EC₅₀ and the maximal current produced by etomidate were additionally influenced by the α isoform. It is concluded that the subtype of β‐subunit influences the potency with which etomidate potentiates GABA‐evoked currents and that the β isoform is a crucial determinant of the GABA‐mimetic activity of this compound. The nature of the α‐subunit also impacts upon the maximal potentiation and activation that the compound may elicit. Such pronounced influences may aid the identification of the site that recognises etomidate. More generally, these results provide a clear example of structural specificity in anaesthetic action. British Journal of Pharmacology (1997) 120, 749–756; doi:10.1038/sj.bjp.0700927

Several mental illnesses, characterized by aberrant stress reactivity, often arise after early-life adversity (ELA). However, it is unclear how ELA affects stress-related brain circuit maturation, provoking these enduring vulnerabilities. We find that ELA increases functional excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, resulting from disrupted developmental synapse pruning by adjacent microglia. Microglial process dynamics and synaptic element engulfment were attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor MerTK. Accordingly, selective chronic chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Notably, selective early-life activation of ELA microglia normalized adult acute and chronic stress responses, including stress-induced hormone secretion and behavioral threat responses, as well as chronic adrenal hypertrophy of ELA mice. Thus, microglial actions during development are powerful contributors to mechanisms by which ELA sculpts the connectivity of stress-regulating neurons, promoting vulnerability to stress and stress-related mental illnesses.

Catching primal functional changes in early, ‘very far from disease onset’ (VFDO) stages of Huntington’s disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca²⁺ imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington’s disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington’s disease pathogenesis long before the onset of clinical symptoms.